Crystal structure of a 1:1 cocrystal of nicotinamide with 2-chloro-5-nitrobenzoic acid

In the 1:1 cocrystal of nicotinamide and 2-chloro-5-nitrobenzoic acid, the molecules form hydrogen bonds through O—H⋯N, N—H⋯O, and C—H⋯O interactions along with N—H⋯O dimer hydrogen bonds of nicotinamide. Further additional weak π–π interactions stabilize the molecular assembly of this cocrystal.


Chemical context
Nicotinamide (NIC) derivatives are used in various applications, for example, in the prevention of type 1 diabetes (Elliott et al., 1993) and nicotinamide cofactors are also used in preparative enzymatic synthesis (Chenault & Whitesides, 1987). The nicotinamide formulation has also been used for treatment in palliative radiotherapy (Horsman et al., 1993). The pharmacological result for the active pharmaceutical ingredient (API) will increase if it becomes cocrystallized with a coformer or other active component (Schultheiss & Newman, 2009;. Chlorobenzoic acid derivatives are widely used in the pharmaceutical industry. 2-Chloro-4-nitrobenzoic acid is used for immunodeficiency diseases as an antiviral and anticancer agent . In the title compound, NIC is cocrystallized with the CNBA coformer as it acts as an excellent candidate for cocrystallization because of the hydrogen-bond acceptor and donor parts (Dragovic et al., 1995).

Structural commentary
The title compound CNBA-NIC (1:1) crystallizes in the monoclinic space group P2 1 /c with four molecules of NIC and The asymmetric unit of the title compound, showing 50% probability ellipsoids, the atom labelling and hydrogen bonding with dotted lines.
CNBA in the unit cell. The dihedral angle between the amide plane with the mean plane of the phenyl part in NIC is 23.87 (1) , and the dihedral angles of the carboxyl and nitro groups with the chlorophenyl ring in CNBA are 24.92 (1) and 3.56 (1) , respectively. In the asymmetric unit, an (CNBA)O-HÁ Á ÁN interaction plays a prime role in the molecular recognition of this cocrystal (Fig. 1).

Supramolecular features
In the crystal structure of the title cocrystal, a strong  Hydrogen bonds in the title compound showing the dimer formation through N-HÁ Á ÁO interactions and tetramer formation through C-HÁ Á ÁO interactions.

Figure 4
Hirshfeld surfaces developed on (i) d norm mapped over the pure NIC molecule, (ii) d norm mapped over the NIC molecule in title compound, (iii) d norm mapped over the pure CNBA molecule and (iv) d norm mapped over the CNBA molecule in title compound.

Figure 3
Weakinteractions stabilize the molecular assembly of both molecules in the crystal.
hydrogen bonds are observed ( Fig. 2 and Table 1). In this cocrystal, the NIC molecule forms a dimer with itself having an R 2 2 (8) graph-set motif (Etter et al., 1990). These dimers are further connected via C-HÁ Á ÁO hydrogen bonding and form a tetrameric ring with two molecules each of NIC and CNBA with R 2 2 (10) graph-set motifs (Etter et al., 1990) (Fig. 2). Furthermore, weakinteractions are observed for both NIC [3.68 (7) Å ] and CNBA [3.73 (7) Å ] which stabilize the molecular assembly along the bc plane (Fig. 3 Figure 5 Two-dimensional fingerprint plots and relative contributions of various interactions to the Hirshfeld surface of the NIC cocrystal molecule.

Hirshfeld surface analysis
To understand the role of intermolecular interactions, we have utilized the Hirshfeld surface analysis visualizing tool (Spackman & Jayatilaka, 2009). The Hirshfeld surfaces and two-dimensional fingerprint plots developed using Crystal-Explorer (Version 3.1; Wolff et al., 2012) are shown in Fig. 4. The red spot on the surface represents a strong interaction through O-HÁ Á ÁN and N-HÁ Á ÁO hydrogen bonding, whereas the blue color represents a lack of interaction. The d norm map of the title compound NICÁCNBA and its pure components is shown in Fig. 4, where individual molecular interactions were estimated. The fingerprint plot shows that OÁ Á ÁH/HÁ Á ÁO and HÁ Á ÁH contribute the major part of the interaction in all compounds (Fig. 4) Two-dimensional fingerprint plots and relative contributions of various interactions to the Hirshfeld surface of the pure NIC molecule. Groom et al., 2016) found no hits. However, searches for NIC and CNBA gave 237 and 9 hits, respectively. A search for the NIC molecule showed that the N atom on the phenyl ring forms strong O-HÁ Á ÁN hydrogen bonds with a carboxyl H atom in the most of the cocrystals [ABULIU (Lou & Hu, 2011), BICQAH (Aitipamula et al., 2013), BICQEL (Aitipamula et al., 2013), BOBQUG (Zhang et al., 2013), CUYXUQ , DINRUP (Lemmerer et al., 2013), DINSEA (Lemmerer et al., 2013), EDAPOQ (Orola & Veidis, 2009) etc]. For the CNBA search, two structures were found similar to the title compound where strong hydrogen bonding is formed by the carboxyl H atom with a pyridine N atom [AJIWIA (Gotoh & Ishida, 2009) and OCAZAT (Ishida et al., 2001)]. AJIWIA also shows halogen bonds through C-OÁ Á ÁCl bonding and forms a dimer through C-HÁ Á ÁO hydrogen bonding.

Synthesis and crystallization
All the chemicals used for the synthesis were purchased from Alfa Aesar and used without further purification. A stock solution was prepared from an equimolar mixture of 2-chloro-5 nitrobenzoic acid (82.44 mg, 0.409 mmol) and nicotinamide (50 mg, 0.409 mmol) in a minimum amount of ethanol and made up to a volume of 10 ml. Ten different combinations of the mixture were prepared using ethanol-hexane as the solvent mixture over the ratio range 1:1 to 1:10. The mixture was kept in a 5 ml beaker and covered with parafilm, with four Two-dimensional fingerprint plots and relative contributions of various interactions to the Hirshfeld surface of the CNBA cocrystal molecule.
to five small holes in it. These solutions were allowed to evaporate slowly at room temperature (27 C) over several days to obtain single crystals. After a few days, colourless crystals were obtained from ethanol-hexane solutions with concentration ratios of 1:10, 1:2 and 1:4. The melting point of the obtained crystal was 159.7 C.

Refinement
Crystal data, data collection, and structure refinement details are summarized in Table 2. All H atoms were found in a difference Fourier maps and were refind freely.  program(s) used to solve structure: SHELXS18 (Sheldrick, 2015); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009) and PLATON (Spek, 2009).

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Single-crystal X-ray diffraction data were collected on a Bruker KAPPA APEX II DUO diffractometer using graphite-monochromated Mo-Kα radiation (λ = 0.71073Å) (Bruker, 2012). The data collection was performed at 153 (2) K. The temperature was monitored by an Oxford Cryostream cooling system (Oxford Cryostat). the program SAINT (Bruker, 2012) were used for cell refinement and data reduction. The data were scaled and absorption correction performed using SADABS (Bruker, 2001). The structure was solved by direct methods using SHELXS-18 (Sheldrick, 2015) and refined by full-matrix least-squares methods based on F2 using SHELXL-2018/3 (Sheldrick, 2015). The computing , Mercury (Macrae et al., 2008) and PLATON (Spek, 2009) were used for molecular graphics and molecular interactions. All non-hydrogen atoms were refined anisotropically.